1、HAART所致的血脂异常和胰岛素抵抗,北京佑安医院 高艳青,抗病毒治疗之前，HIV/AIDS人群HDL & LDL (especially HDL) 下降，而甘油三酯水平升高。HAART后LDL和总胆固醇升高,甘油三酯 也升高。大部分的蛋白酶抑制剂、核苷类药物、部分非核苷类药物可引起脂代谢异常，但程度不同。,HIV/ART 毒性: 血脂异常,1. Schambelan M et al. JAIDS 2002; 31(3):257-75.2. 11th CROI, 2004, Abstract 739.,3. 11th CROI, 2004, Abstract 736.4. 11th CROI,
2、 2004, Abstract 737.,大型临床试验,CASTLE: ATV/RTV vs LPV/RTV at Week 48,TC,LDL,HDL,Non-HDL,TG,Median Change From BL (%),*P .0001,ATV/RTV + TDF/FTC (n = 440),LPV/RTV + TDF/FTC (n = 443),Difference estimates (%),-9.5,-2.9,-3.8,-11.6,-25.2,0,10,20,30,40,50,60,*,*,*,Molina JM, et al. CROI 2008. Abstract 37.,E
3、ron JJ, et al. Lancet. 2006;368:476-482.,KLEAN: FPV/RTV vs LPV/RTV at Week 48对脂代谢的影响,39,39,29,60,33,41,23,66,0,20,40,60,80,100,TC,HDL,LDL,TG,FPV/RTV 700/100 mg BID +ABC/3TC (n = 434),LPV/RTV SGC 400/100 mg BID +ABC/3TC (n = 444),Median Change From BL (%),Lipid effects comparable between arms,ARTEMIS
4、: DRV/RTV 和 LPV/RTV对血脂的影响比较,De Jesus E, et al. ICAAC 2007. Abstract 718b.,100,200,Mean TG Level ( SE),Time (Wks),343 320 306346 313 301,DRV/RTV n =LPV/RTV n =,LPV/RTV + TDF/FTC,Mean TC:HDL Ratio ( SE),5.0,4.0,3.0,4.5,3.5,1.1,2.3,1.7,2.9,NCEP cutoff,mM,ng/mL,250,150,2,4,8,12,16,24,36,48,DRV/RTV + TDF
5、/FTC,2,4,8,12,16,24,36,48,343 320 305346 313 301,Time (Wks),TG,TC:HDL Ratio,BMS-034 & BMS-089: 激动剂的阿扎那韦和无激动剂的 ATV 在48周对血脂的影响,*P .0001,TC,LDL,HDL,Median Change From BL (%),ATV + ZDV/3TC (n = 404),EFV + ZDV/3TC (n = 401),0,10,20,30,40,50,2,21,1,18,13,24,*,*,*,1. Squires K, et al. J Acquir Immune Defic
6、 Syndr. 2004;36:1011-1019.2. Malan DR, et al. J Acquir Immune Defic Syndr. 2008;47:161-167.,TC,LDL,HDL,Median Change From BL (%),ATV + d4T + 3TC (n = 105),ATV/RTV + d4T + 3TC (n = 95),0,10,20,30,40,50,7,16,16,24,24,25,BMS-0341,BMS-0892,van Leth F, et al. PLoS Med. 2004;1:e19.,非核苷类药物对血脂的影响： EFV vs NV
7、P at Week 48,48周, 多中心, 开放, 随机 未治疗 (N = 1216)NVP 400 mg QD (n = 220)NVP 200 mg BID (n = 387)EFV 600 mg QD (n = 400)NVP 400 mg + EFV 800 mg QD (n = 209)All plus d4T + 3TCEFV组血脂变化较大 (combination NVP + EFV arm excluded from lipid analysis),*P .05 vs NVP.P .001 vs NVP.,Mean Change in Lipids From Baseline
8、 to Week 48 (%),*,-10,0,10,20,30,40,50,TC,LDL,HDL,TG,TC:HDL,EFV + 3TC/d4T,Pooled NVP + 3TC/d4T,31,27,40,35,34,43,49,20,5.9,-4.1,GS 934 and GS 903: TDF与嘧啶类似物对血脂的影响,1. Arribas J, et al. J Acquir Immune Defic Syndr. 2008;47:74-78. 2. Gallant JE, et al. JAMA. 2004;292:191-201.,前瞻性, 随机, 双盲研究TDF 对血脂水平影响较小
9、,HEAT: ABC/3TC vs TDF/FTC at Week 48对血脂的影响,32,13,8,64,23,11,-1,38,-20,0,20,40,60,80,TC,HDL,LDL,TG,ABC/3TC + LPV/RTV (n = 343),TDF/FTC + LPV/RTV (n = 345),Median Change From BL (%),Smith K, et al. CROI 2008. Abstract 774.,Lipid effects comparable between arms,易导致高脂血症的抗病毒药物,蛋白酶抑制剂：洛匹那韦，利托那韦，茚地那韦，FPV非核
10、苷类：依非韦伦核苷类药物:TDF对血脂的影响较小。,是否可以间断抗病毒治疗以减少心血管疾病的发生率？,在5472名HIV/AIDS 中比较了持续和间断抗病毒治疗对心血管疾病发生的影响。结果表明，传统的危险因素如糖尿病、高血压显著增加心血管疾病的发生，除此之外，间断的抗病毒治疗也是一个重要因素。间断抗病毒人群的D-二聚体和白介素-6水平显著升高。ACTG(AIDS Clinical Trials Group)A5102试验进一步发现，尽管间断抗病毒治疗有益于降低TC、TGs、LDL水平，但所有这一切最终被HDL-C 的持续低水平所抵消，最终导致了心血管发病率上升。,SMART: 间断的抗病毒治疗
11、增加了心血管疾病的发生率,是否应该减少或停止应用激动剂？,Boosted vs Unboosted PIs,低剂量的RTV增效, 减少给药次数, 减少耐药增加了代谢副作用,*All RTV 200 mg/day except TPV requires RTV 400 mg/day,BMS-089: ATV/RTV对ATV在96周的结果,AI424-089: 随机、开放、多中心临床研究 ATV 400 mg QD (n = 105)ATV/RTV 300/100 mg (n = 95)Both with d4T XR 100 mg QD + 3TC 300 mg QDATV组更易出现耐药*ATV
12、/RTV vs ATV对血脂水平影响更显著Median lipid levels did not meet intervention levels at Week 96,Malan DR, et al. J Acquir Immune Defic Syndr. 2008;47:161-167.,*Not powered to determine if ATV noninferior to ATV/RTV.,Change From Baseline Median Lipid Levels (%),20,33,27,35,7,23,14,19,10,20,30,40,TC,HDL,FastingL
13、DL,FastingTG,ATV/RTV 300/100,ATV 400,Change in Median Lipid Levels From Baseline to Week 96,P .01,P .05,0,HIV阴性人群的LDL目标也适用于HIV人群,如何处理HAART相关的高脂血症? 改变抗病毒方案还是服用降脂药?,Carr A, et al. AIDS. 2001;15:1811-1822. Moyle G, et al. AIDS. 2001;15:1503-1508. Miller J, et al. AIDS. 2002;16:2195-2200. Doser N, et al
14、. AIDS. 2002;16:1982-1983. Aberg JA, et al. AIDS Res Hum Retroviruses. 2005;21:757-767. Calza L, et al. AIDS. 2005;19:1051-1058.,更换抗病毒药物还是服用降脂药？,何时更换抗病毒药物保持病毒学抑制是最重要的换药有可能会导致病毒反弹降脂药物可避免换药的危险性 但药物负担加重更常在美国应用; 欧洲的指南仅在饮食控制和更换药物无效时才启动,*P .001 for comparison with time of switch.,Mean Change in Fasting Li
15、pids (mg/dL),*,*,102,41,59,38,0,20,40,60,80,100,120,Baseline (Time of Switch),Year 3,GS903E: From d4T to TDF (Week 144)血脂变化,Madruga JVR, et al. ICAAC 2007. Abstract H-364.,N = 85,TG,TC,Mallolas J, et al. IAS 2007. Abstract WEPEB117LB.,ATAZIP: From LPV/RTV to ATV/RTV,TG,LDL,HDL,TC,-60,-40,-20,0,20,P
16、.0001,Change at Week 48 (mg/dL),P 6 months 随机分为 LPV/RTV 400/100 mg BID (n = 127) or换为 ATV/RTV 300/100 mg QD (n = 121),降脂药物和更换抗病毒药物,12个月，开放性研究 130 patients; 60% male; mean age: 39 years分组PI EFV (n = 34)PI NVP (n = 29)Add bezafibrate (n = 31)加普伐他汀(n = 36)普伐他汀和贝特类药物降脂更有效，相对于更换抗病毒药物。,Calza L, et al. AID
17、S. 2005;19:1051-1058.,0,3,6,9,12,Months,350,300,250,200,150,100,50,0,0,3,6,9,12,Months,Mean Plasma TGs(mg/dL),Mean Cholesterol(mg/dL),350,300,250,200,150,100,50,0,对于在boosted PIbased的患者单纯TG升高，如何处理？,高甘油三酯的处理,NCEP ATP III final report. Circulation. 2002;106:3143-3421.,基本干预：饮食控制考虑换用抗病毒药物如果 TG 500-1000 m
18、g/mL ( 5.65-11.30 mmol/L) 并且不可能更换药物时，考虑贝特类药物Gemfibrozil 600 mg BID or fenofibrate 200 mg QD associated ，可降低2050的TG如果高脂血症仍未控制鱼油 (up to 6 g/day) 或 烟酸 500 mg QD ，烟酸可以增加胰岛素抵抗。,药物之间的相互作用在服用抗病毒药物的患者中非常重要，如何安全应用？,降脂药和蛋白酶抑制剂之间的相互作用,*AUC with DRV.,Aptivus package insert; 2005. Carr RA, et al. ICAAC 2000. Abs
19、tract 1644. Fitchenbaum CJ, et al. AIDS. 2002;16:569-577. Gerber JG, et al. CROI 2004. Abstract 603. Gerber J, et al. IAS 2003. Abstract 870. Hsue PH, et al. Antimicrob Agents Chemother. 2001;45:3445-3450. Lexiva package insert; 2007. Prezista package insert; 2006. Reyataz package insert; 2007.,生活方式
20、: 饮食和体育锻炼是否同样适用于HIV阳性人群？,饮食控制降低HIV人群心血管疾病的发生率,膳食中过多的动物蛋白会导致TC (P .01)升高, TG(P .01)升高, HDL (P .001) 降低高膳食纤维尤其是可溶性纤维, 可以升高HDL水平降低脂肪沉积。,1. Shah M, et al. HIV Med. 2005;6:291-298.2. Hendricks KM, et al. Am J Clin Nutr. 2003;78:790-795.3. Wohl DA, et al. Clin Infect Dis. 2005;41:1498-1504.,体育锻炼降低HIV人群心血管
21、疾病的发生危险,二甲双胍 vs 二甲双胍体育锻炼 in 25 HIV-infected patients二甲双胍 锻炼 显著地改善心血管参数 vs 二甲双胍Waist-to-hip ratios 下降 (P = .026)静息状态下收缩压下降 (P = .012)静息状态下舒张压下降 (P = .001)Changes in fasting insulin and insulin AUC more significant with metformin and exercise vs metformin alone (P 2.5 x ULN 应避免使用 罗格列酮肝毒性增加血肌酐水平升高的患者应避免使用 二甲双胍。易导致乳酸血症,AACTG Metabolic Guides. Available at: http:/aactg.s- Accessed March 10, 2008.,谢 谢！,
